Creating Awareness for Primary Immunodeficiencies in Japan

Inborn errors of immunity (IEIs) are a heterogeneous group of disorders, genetically diverse but phenotypically overlapping. Over 500 IEI-related genes have been identified. Next generation sequencing (NGS) enables the simultaneous evaluation of a large number of genes in multiple patients in parallel. Since 2017, in our setting, custom IEI panels have been useful mainly for patients displaying clinical phenotypes of immune dysregulation and autoinflammatory disorders. Our aim is to evaluate the performance of targeted NGS panels based on International Union of Immunological Societies (IUIS) gene categories by examining how many patients achieved a conclusive diagnosis. A retrospective analysis was performed on 361 index cases submitted to four chronologically successive targeted NGS custom panels. The first panel included 124 IUIS genes, most of them related to autoimmune and immune dysregulation disease categories. The second panel contained 143 IUIS genes, including defects of innate immunity. The third and fourth, large panels covering 314 and 325 IUIS genes, respectively, included/comprised the majority of IUIS disease categories, with focus on autoinflammatory, immune dysregulation, and intrinsic immunity disease categories. From a total of 361 samples studied, 264 were referred due to clinical suspicion of immune dysregulation, autoinflammatory disease, or defects in innate immunity. Twenty-three percent of them (61/264) achieved a confirmed or highly probable genetic etiology. According to the main IEI IUIS disease categories included in targeted panels, immune dysregulation represented 26% (32/123) of these diagnoses, autoinflammatory disorders 21% (18/85), and defects in innate immunity 19% (11/56). In the remaining patients studied, 42% (41/97) of them achieved a conclusive diagnosis in others IEI IUIS disease categories. The NGS approach demonstrated the expected IEI diagnostic rate. The strategy of designing panels oriented toward IEI disease categories that present the greatest variability in clinical presentations with overlapping phenotypes proved to be effective regarding achievement of conclusive diagnoses in our cohort.

We present to Russian-speaking audience a translation and commentary on the classification of inborn errors of immunity presented at the end of 2019 by the Committee on Congenital Immunity Errors at the International Union of Immunological Societies (IUIS). Inborn errors of immunity, or, as they were called earlier, primary immunodeficiencies, is a rapidly expanding class of diseases that includes the most diverse congenital pathologies which can manifest at any age by heterogenous symptomes. Clinical masks characterize these diseases, hence the time from the onset of clinical disorder to the final diagnosis may take many years. A doctor of any specialty encounters these patients, and the molecular mechanisms of pathology concern different organs and systems of the patients. The classification consists of ten tables covering more than 400 syndromes and their corresponding genes, or associated chromosomal abnormalities. This is a tool, which allows navigating a wide variety of different primary immunodeficiencies, autoimmune and autoinflammatory syndromes, complement defects, and bone marrow failure syndromes. We hope that, due to translation, current knowledge about these various diseases will become more close and available to the Russian-speaking audience.

The field of primary immunodeficiencies (PIDs) is rapidly evolving. Indeed, the number of described diseases is constantly increasing thanks to the rapid identification of novel genetic defects by next-generation sequencing. PIDs are now rather referred to as “inborn errors of immunity” due to the association between a wide range of immune dysregulation-related clinical features and the “prototypic” increased infection susceptibility. The phenotypic spectrum of PIDs is therefore very large and includes several orofacial features. However, the latter are often overshadowed by severe systemic manifestations and remain underdiagnosed. Patients with impaired innate immunity are predisposed to a variety of oral manifestations including oral infections (e.g., candidiasis, herpes gingivostomatitis), aphthous ulcers, and severe periodontal diseases. Although less frequently, they can also show orofacial developmental abnormalities. Oral lesions can even represent the main clinical manifestation of some PIDs or be inaugural, being therefore one of the first features indicating the existence of an underlying immune defect. The aim of this review is to describe the orofacial features associated with the different PIDs of innate immunity based on the new 2019 classification from the International Union of Immunological Societies (IUIS) expert committee. This review highlights the important role played by the dentist, in close collaboration with the multidisciplinary medical team, in the management and the diagnostic of these conditions.

The aim of this study was to screen for inborn errors of immunity (IEIs) within a pediatric critical care population and further evaluate the mortality-related factors.This study included 1203 pediatric patients aged between 1 month and 18 years admitted to the pediatric intensive care unit (PICU) at Antalya Education and Research Hospital (in Turkey) between January 2020 and December 2022. Patients with chronic diseases, ongoing chronic medication regimens, other known comorbidities, traumas, postsurgical cases, poisonings, and preexisting IEI diagnoses were excluded.In this single-center prospective study, a total of 28 warning signs for IEI diagnosis were applied, including 10 per the Jeffery Modell Foundation (JMF) and 18 per literature review. Patients with severe illness requiring intensive care and at least 1 IEI warning sign were evaluated. These patients underwent standardized immunological screening, then those with abnormal findings had an extended immunologic assessment including functional analyses. Genetic analyses were conducted on those with abnormal findings concerning for IEI. Diagnoses of IEI were established using the European Society for Immunodeficiencies criteria and further categorized based on the International Union of Immunological Societies classification.Of the 1203 patients admitted to the PICU, 75 (6.2%) patients had at least 1 IEI warning sign and no exclusionary diagnoses. This study found a 4.3% confirmed IEI prevalence rate in the PICU during the 3-year study period. More than half (51.5%) of these patients presented with sepsis, 36.4% with acute respiratory failure, and 12.1% with neuroinflammatory disorders. The median age was 16 months, and there was a male predominance (60.6%). Consanguinity was present in 66.7% of the patients. History of severe viral infections was the most common IEI warning sign (61%), followed by life-threatening infections (51.7%), sibling/cousin death (25%), and a history of more than 2 episodes of pneumonia per year (22.5%). Only 31% of patients had 2 or more of the JMF warning signs. Regarding types of IEIs identified, nearly half (48.5%) were diagnosed with an immune dysregulation disorder, with the most prominent IEI diagnosis being hemophagocytic lymphohistiocytosis. Combined immunodeficiencies were also commonly identified (24.2%), followed by defects in innate immunity (15.2%) and predominant antibody deficiencies (6.1%). Genetic testing was performed on 78.8% (26/33) of patients with an IEI diagnosis. Among the 33 patients with confirmed IEI, the mortality rate was 58%.Patients with IEI can present critically ill without classic warning signs and have a high mortality rate. This highlights the need for systematic screening to reach early diagnosis and treatment, especially in critically ill children.This study highlights a significant yet underrecognized prevalence of IEI in PICUs. The identification of IEI in nearly 1 in 20 critically ill children and reported high mortality rate of 58% emphasizes the need for earlier screening and detection with targeted immunologic/genetic evaluation. The study also found that only 31% of patients exhibited 2 or more JMF warning signs, suggesting a need for wider criteria, especially in the PICU. Limitations of the study include a single-center study in a country with high consanguinity, thus limiting generalizability. There was a small sample size of only 33 patients with new IEI diagnosis, and data were limited to their hospitalization without long-term follow-up related to mortality. Despite these limitations, this study reinforces that IEIs are more common than traditionally thought and general pediatricians, as well as PICU specialists, have a critical role in early suspicion, diagnosis, and seeking immunology consultation to reduce mortality and long-term morbidity.

Background: Due to the absence of curative treatments for inborn errors of immunity (IEI), children born with IEI require long-term follow-up for disease manifestations and related complications that occur over the lifespan. Effective transition from pediatric to adult services is known to significantly improve adherence to treatment and long-term outcomes. It is currently not known what transition services are available for young people with IEI in Europe. Objective: To understand the prevalence and practice of transition services in Europe for young people with IEI, encompassing both primary immunodeficiencies (PID) and systemic autoinflammatory disorders (AID). Methods: A survey was generated by the European Reference Network on immunodeficiency, autoinflammatory, and autoimmune diseases Transition Working Group and electronically circulated, through professional networks, to pediatric centers across Europe looking after children with IEI. Results: Seventy-six responses were received from 52 centers, in 45 cities across 17 different countries. All services transitioned patients to adult services, mainly to specialist PID or AID centers, typically transferring up to ten patients to adult care each year. The transition process started at a median age of 16–18 years with transfer to the adult center occurring at a median age of 18–20 years. 75% of PID and 68% of AID centers held at least one joint appointment with pediatric and adult services prior to the transfer of care. Approximately 75% of PID and AID services reported having a defined transition process, but few centers reported national disease-specific transition guidelines to refer to. Conclusions: Transition services for children with IEI in Europe are available in many countries but lack standardized guidelines to promote best practice.

What’s the ‘Skinny’ on Microbiome? Interplay of Immune Cells, Microbes, and Skin Barrier in Health and Disease

Structural skeletal abnormalities are associated with primary immunodeficient (PID) patients. These abnormalities have not been well studied in PID with reference to osteopathic medicine tenets. Osteopathic structural examinations of PID patients with respect to these tenets and the diagnosis of somatic dysfunctions preventing the free flow of lymph fluids back into the circulation and the disruption of the skeletal microenvironment may have an impact on the status of the immune system in patients with a PID. A standardized evaluation was conducted in a patient with a phosphatidylinositol 3-kinase regulatory subunit 1 (PIK3R1) mutation who presented with skeletal abnormalities. A literature review was also conducted to determine the breadth of other PIDs with structural irregularities. Osteopathic structural clinical examinations (OSCEs) were performed by an osteopathic medical student, fellow, and attending after receiving informed consent from the patient. The findings were collected regionally noting severity, tissue texture changes, asymmetry, altered range of motion (ROM), and tenderness according to DO-Touch.NET physical examination and treatment form. A literature review was conducted utilizing various search engines and the textbook, Stiehm's Immune Deficiencies, 4th edition. The significant findings found from the patient were right sidebending rotation cranial strain pattern with decreased left temporal bone motion, temporomandibular joint crepitus, and right deviation upon mandibular opening. The thoracolumbar region revealed tissue tenderness and restricted psoas ROM. Bilateral sacroiliac joint tenderness, right superior sheering, and anterior innominate rotation, along with left-on-left sacral flexion, were associated with valgus knees. The literature search showed multiple other PIDs outside of PIK3R1 that have associated skeletal and structural abnormalities. Irregular skeletal features found in immunodeficient patients may have an additive defect on the immunological responses due to somatic dysfunction impinging on the lymphatic flow to the central circulation. Other different immunodeficient patients suffer from boney structural abnormalities, which may lead to further immune hindrance caused by impingement of flow as well as bone marrow microenvironment impact on the peripheral immunological output. We present the first osteopathic examination with detailed findings of somatic dysfunction in a patient with PID. Future studies on PID patients should require more attention to structure and function, as found by a thorough osteopathic examination in order to unrestrict preformed cellular and humoral components back into the peripheral circulation.

The study presents an overview on current situation of primary immunodeficiency (PID) patients in Poland and the 2014 annual report of the Polish Working Group for Immunodeficiency (PWGID). The group was set up in 2005 to improve diagnosis, treatment, and care of patients with immunodeficiencies and currently includes 15 pediatric and 13 adult centers. According to PWGID report 4099, PID patients are recognized in Poland, with the prevalence 10.6/100,000. The majority of them (54.2%) have predominantly antibody deficiency (PAD). In 2014 alone, a total number of 731 newly diagnosed individuals are reported. As predicted, the vast majority (70%) of them have PAD. Approximately one third of PAD patients require immunoglobulin replacement therapy. Within the entire cohort, an intravenous route of immunoglobulin therapy dominates (67.3%). However, within the age groups, distribution of immunoglobulin therapy varies and seems to be age related. Among children, 36% receive subcutaneous immunoglobulin, while with adults 26%. Analysis of numbers of either newly recognized or treated patients indicates its dynamic increase in recent years. This is the result of comprehensive activities by PWGID supported by governmental institutions, outstanding foundations, and patient's organization. • Immunoglobulins' treatment has substantially changed the life of individuals with PAD. Patients with common variable immunodeficiency (CVID) or X-linked agammaglobulinemia (XLA) can live and lead a near normal life. Early diagnosis of the disease followed by earlier implementation of appropriate treatment, including gammaglobulin replacement therapy, improves the quality of life. • Targeted efforts of health care professionals and government are required to optimize diagnostic and therapeutic approach for PAD. What is New: • Comprehensive activities of PWGID lead to better recognition of PID individuals and should improve reporting Polish PIDs to the ESID database. • Following the joint efforts of immunologists, patient's, and governmental organizations in the end of 2014, the Therapeutic Program for Treatment Adults with PID was introduced, leading to universal access to currently available treatment options and to improve the quality of life.

EVALUATING BEHAVIORAL PROBLEMS IN PATIENTS WITH PRIMARY IMMUNODEFICIENCY DISORDERS WITHIN THE US IMMUNODEFICIENCY NETWORK REGISTRY

Introduction: Inborn error of immunity (IEI) includes variety of genetic disorders that affect both the innate and acquired immune system. The number of primary immune deficiency disorders is increasing due to advanced laboratory testing methods. The patients with IEI are susceptible to multiple infectious and non-infectious diseases، including autoimmune disorders، allergies، and malignancies. Several studies have shown an increasing prevalence of non-infectious disorders in patients in IEI. Among the non-infectious manifestations of primary immunodeficiency، allergic symptoms can play an effective and important role in diagnosis and treatment of these patients.
 Methods: Articles were searched in Google Scholar، PubMed، Web of Science، and Scopus databases. In this review، we have tried to use the latest and most reliable articles related to the subject that have been published in Persian and English language.
 Conclusion: Allergic diseases can be a common part of some primary immunodeficiency diseases. Even in some types of primary immunodeficiency، they are considered the main symptom and important indicator of the disease، which are very decisive factors for the diagnosis of immunodeficiency.

Background: Inborn errors of immunity (IEIs) are a heterogeneous group of genetically determined disorders that lead to immune dysfunction, recurrent infections, and organ-specific complications. The lungs are among the most commonly affected organs, with both infectious and noninfectious manifestations that significantly contribute to morbidity and mortality. This study aimed to provide a comprehensive overview of pulmonary manifestations in IEI, with emphasis on pathophysiological mechanisms, diagnostic approaches, and therapeutic strategies. Methods: A narrative review and synthesis of current literature and clinical guidelines were conducted, focusing on pulmonary involvement in IEI as classified by the International Union of Immunological Societies (IUIS). The analysis included data on infectious and noninfectious complications, imaging findings, immunological assessments, and management strategies, supported by clinical evidence and expert consensus. Results: Pulmonary manifestations in IEI encompass a wide spectrum of conditions. Infectious complications include recurrent bacterial pneumonias, bronchitis, and opportunistic infections, frequently resulting in irreversible lung damage such as bronchiectasis. Noninfectious complications, including granulomatous–lymphocytic interstitial lung disease (GLILD) and interstitial lung disease (ILD), are common in disorders such as common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA). Early diagnosis using high-resolution computed tomography (HRCT) and immunological testing, combined with the timely initiation of immunoglobulin replacement therapy and anti-biotic prophylaxis, significantly improves prognosis. Conclusions: Pulmonary complications are key clinical indicators of IEI and often precede systemic manifestations. Early, integrated, and interdisciplinary diagnostic and therapeutic management are crucial for preventing irreversible lung damage and improving patient outcomes. Regular monitoring and individualized therapy, including immunoglobulin replacement, targeted immunosuppression, and vaccination, are the cornerstones of effective long-term care in IEI.

Subclinical infection and dosing in primary immunodeficiencies.

Inborn errors of immunity (IEIs) can exhibit variant clinical manifestations beyond the classic presentation of recurrent infections. Allergic diseases represent an important subset that can arise as the primary feature or coexist with IEIs. In this study, we aimed to investigate the burden of the most frequent allergic diseases among individuals with primary immune deficiency. Over 70 registered patients with a definite diagnosis of IEI were enrolled in our study. Patients and their records were evaluated, and data were collected via a questionnaire. Additionally, laboratory investigations, including spirometry, skin prick tests, and specific IgE, were used to confirm the diagnosis of allergic diseases. Statistical analysis was performed via SPSS software. The most frequent IEIs in our study comprise agammaglobulinemia, hyper-IgE syndrome, and common variable immune deficiency. The overall prevalence of allergic diseases among IEI patients was 77.8%. Allergic rhinitis, with a prevalence of 47.2%, atopic dermatitis 40.3% and asthma 37.5% were the most frequent allergic diseases among these patients. The highest prevalence of allergic rhinitis and asthma was detected among patients with agammaglobulinemia (23.5% and 33.5%). Also, Atopic dermatitis and food allergy had the highest prevalence in hyper IgE syndrome (27.6% and 75%). Agammaglobulinemia was accounted for as the most frequent IEI accompanying allergic disorders in our study. The interplay between atopy and IEIs is complex, highlighting the role of immune dysregulation in allergic diseases. Our study investigated the prevalence of allergic diseases among individuals with inborn errors of immunity. According to the coexistence of allergic diseases and IEIs, in patients with unusual, early onset, and severe allergic manifestations, underlying IEI may be suspected.

The immune system protects the body. When defenses are compromised, people with hereditary immunological disorders become vulnerable to many life-threatening infections. Inborn errors of immunity (primary immunodeficiencies), manifested in patients in increased susceptibility to infectious diseases, autoimmune diseases, allergies, and malignant neoplasms. Today, this group of diseases is still considered quite rare. However, the development of diagnostic technologies expands the list of nosologies associated with inborn errors of immunity. Neonatal screening for inborn errors of immunity could solve many of the problems of these patients, but the procedure is not carried out in the Russian Federation. Therefore, diagnostics based on an analysis of the clinical manifestations of diseases. In most cases, the disease is diagnosed in early childhood. Here, the role of both the parents of the child-patient and the medical staff is important. The health and life of the child depends on their awareness of the disease, methods of diagnosis, treatment. This group of diseases is chronic, under an hour, severe. In the absence of timely diagnosis and proper therapy, it can be fatal. The article describes the experience of applied quantitative research conducted by the method of questioning patients with primary immunodeficiencies (parents of underage patients), about their disease, methods of treatment, problems arising in the long-term struggle with this complex disease. The author notes that patients and primary care doctors or general practitioners are poorly informed about diseases associated with primary immunodeficiencies. It is concluded that it is necessary to increase the informational medical culture of the population, especially the young, as participants in the interaction "doctor-patient" and representatives of the interests of minor children-patients with inborn errors of immunity.

Inborn errors of immunity (IEI) or primary immune deficiencies (PIDD) are caused by variants in genes encoding for molecules that are relevant to the innate or adaptive immune response. To date, defects in more than 450 different genes have been identified as causes of IEI, causing a constellation of heterogeneous clinical manifestations ranging from increased susceptibility to infection, to autoimmunity or autoinflammation. IEI that are mainly characterized by autoinflammation are broadly classified according to the inflammatory pathway that they predominantly perturb. Among autoinflammatory IEI are those characterized by the transcriptional upregulation of type I interferon genes and are referred to as interferonopathies. Within the spectrum of interferonopathies, genetic defects that affect the proteasome have been described to cause autoinflammatory disease and represent a growing area of investigation. This review is focused on describing the clinical, genetic, and molecular aspects of IEI associated with mutations that affect the proteasome and how the study of these diseases has contributed to delineate therapeutic interventions.